Obesity arises from increased appetite or ingestion of food over energy requirement. Previous research has identified that the functions of the human stomach are important determinants of fullness while eating, a factor that influences cessation of food intake. Many candidate genes have been associated with development of either obesity (e.g. fat mass and obesity-associated gene, FTO) or type II diabetes mellitus (DM, e.g. TCF7L2). This research proposal seeks to further examine the association of candidate genes with stomach functions (rate of gastric emptying, gastric volume and maximum tolerated volume as a marker of sensitivity) that are associated with fullness while eating. Some candidate genes influence the effectiveness of obesity treatment. In the prior cycle of DK67071, our research team demonstrated, in a randomized controlled clinical trial, that specific markers of three genes controlling adrenergic and serotonergic function (ADR2A, GNB3 and 5- HTTLPR) are significantly associated with weight loss in response to sibutramine. In this proposal, we seek to expand the markers or genetic variants in these genes (ADR2A, GNB3 and 5-HTTLPR) and to explore effects of other genes that are associated with obesity in epidemiological studies (uncoupling proteins [UCP], and FTO, and type II DM [TCF7L2]) on peripheral determinants of satiation and satiety though validated measurements of gastric emptying of solids and liquids by scintigraphy, gastric volume by SPECT, satiation by nutrient drink test and satiety by standardized buffet meal. Our overall, long term aim is to identify susceptibility genes that influence peripheral gastrointestinal functions, reduce satiation and predispose to obesity and that significantly modify weight response to sibutramine. Identifying those genes will also facilitate selection of people who should benefit from new prevention or treatment for obesity directed at the gastrointestinal functions. Our specific aims are: first, to compare maximum tolerated volume, postprandial satiation, gastric emptying, fasting and postprandial accommodation volume in overweight and obese adults with allelic variants at the FTO, ADRB3, uncoupling protein-2, ADR2A, GNB3 loci to adults with common alleles. A second aim is to compare the same functions in non-diabetics, non-obese and adults with impaired fasting glucose who are carriers of the diabetes-associated TCF7L2 allele vs. those with the diabetes-protective allele. A third aim is to assess the pharmacogenetic modulation of weight loss in response to sibutramine 15 mg per day compared to placebo for 12 weeks in obese and overweight adults with allelic variation in the same candidate genes compared to adults with common or disease-protecting alleles. Apart from the specific information about the pharmacogenetics of sibutramine, this research will identify genetic susceptibility to abnormal stomach function that, in the future, may be treated with pharmacotherapy or devices that change gastric function, increase fullness during meals and induce cessation of feeding. Thus, the approach has potential to prevent obesity in those with genetic susceptibility, and to select patients for peripherally targeted weight loss therapies.